Hepatitis is a viral disease that causes inflammation of the liver that may lead to cirrhosis, primary liver cancer and other long-term complications. Nucleosides are a well-recognized class of compounds shown to be effective against a variety of viral infections, including hepatitis B, HIV, and herpes. Several nucleosides are reported to inhibit hepatitis C (HCV) virus replication, including ribavirin, which currently is marketed as a drug combination with various interferons, and the direct acting antiviral agents.
Nucleosides are generally effective as antiviral agents following conversion to the corresponding nucleoside 5′-triphosphate (NTP). Conversion occurs inside cells through the action of various intracellular kinases. The first step, i.e. conversion of the nucleoside to the 5′-monophosphate (NMP) is generally the slow step and involves a nucleoside kinase, which is encoded by either the virus or host. Conversion of the NMP to the NTP is generally catalyzed by host nucleotide kinases. The NTP interferes with viral replication through inhibition of viral polymerases and/or via incorporation into a growing strand of DNA or RNA followed by chain termination.
Use of synthetic nucleosides to treat viral liver infections is often complicated by several problems. In some cases, the desired nucleoside is a good kinase substrate and accordingly produces NTP in the liver as well as other cells and tissues throughout the body. Since NTP production is often associated with toxicity, nucleoside antiviral efficacy can be limited by extrahepatic toxicities. In other cases, the desired nucleoside is a poor kinase substrate which is not efficiently converted into the NMP and ultimately into the NTP. Many nucleosides have poor oral bioavailability and need to be in a prodrug form for oral use.
Ribavirin is orally available and is likely to be absorbed via a group of transporters, which may increase the likelihood of undesirable drug-drug interaction. In human subjects, Ribavirin has a relatively long half-life (˜12 days) and may be sequestered in cells, such as red blood cells, causing anemia and other side effects. Indeed, ribavirin may be sequestered in red blood cells as long as 6-months, namely, the average lifespan of the cells.
A strategy of selectively delivering ribavirin monophosphate into the liver via a transporter independent mechanism would be beneficial to patients who suffer from viral liver diseases due to an increase in the liver concentration of the biologically active ribavirin phosphates, a decrease in concentration of ribavirin outside the liver, and potentially an increase in efficacy in patients having ribavirin transporter deficiency. For example, U.S. Pat. No. 6,312,662 disclose the use of certain phosphate prodrugs for the liver-specific delivery of various drugs including nucleotides for the treatment of patients with liver diseases such as hepatitis C, hepatitis B and hepatocellular carcinoma.